The proposed research is the study of new paradigms in both the treatment of cancer and cancer drug development. This platform technology will markedly expand the number of cancer specific surface receptors and antigens that can be targeted for drug delivery using peptide ligands. The general principle of this new technology is that cancer cells respond to ionizing radiation through a stress response that involves membrane transport and presentation of stress proteins on the cell surface. These proteins are normally sequestered within the cancer cell but are transported to the surface in response to oxidative stress and DNA strand breaks caused by ionizing radiation. We exploit this physiologic response by developing peptide ligands that bind to radiation-inducible stress proteins with high affinity and specificity. Since 1998, the Hallahan lab has identified over 4 dozen radiation-inducible cell surface proteins through the use of platform technologies. To identify candidate ligands for these surface proteins, a phage display library representing over 2 billion peptides was injected into the circulation of mice bearing irradiated cancers. Phage that bound to the irradiated tumor were amplified and injected into another tumor-bearing mouse after irradiation. After 5 passages through irradiated tumors, peptides bind specifically to irradiated cancers. The cell surface receptors for these peptides were identified by proteomic and genomic methods. The resulting peptide ligand-receptor pairs have been prioritized by cancer specificity, prolonged binding and binding to multiple cancer subtypes. The lead radiation inducible receptors that achieve all of these criteria include TIP-1, and GRP-78. To develop drug delivery systems targeting irradiated tumors, we will utilize peptide ligands to the lead receptors we have identified. Conjugation of peptides to therapeutic agents can specifically deliver cytotoxic agents to mouse models of human cancer. With this approach, we have improved tumor control, pharmacokinetics and bioavailability of cancer drugs. We propose research to test the hypothesis that inducible cell-surface proteins on cancer can be exploited to achieve cancer specific drug delivery in patients. We will conjugate the lead peptide to PEG and chelators that will serve to image the spatial and temporal distribution of peptides in planned clinical trials.